Polycystic kidney disease (PKD) is the most common genetically transmitted renal disease. In humans, PKD is inherited in two different modes, an adult, dominant form and an infantile, recessive type. In both forms of this disease, normal kidney tissue is replaced by innumerable cysts which are lined by a hyperplastic epithelium displaying an immature phenotype. The epithelial immaturity could arise from either a genetically programmed immaturity (arrested differentiation) or an induced state of dedifferentiation from which the cells cannot escape. Increased proliferation by these immature cells causes tubule enlargement, i.e. cyst formation. We hypothesize that infantile PKD is caused by arrested differentiation of the collecting duct segment. To test this hypothesis we will evaluate the state of differentiation of the collecting ducts at several time points during the development of inherited and induced forms of infantile PKD. We will use an inherited type of murine PKD (C57BL/6J- cpk/cpk) and an acquired type of infantile PKD (induced by glucocorticoids in neonatal mice and rabbits), to determine if collecting duct cystogenesis has common pathogenic features irrespective of etiology. To evaluate epithelial immaturity, we will use nucleic acid hybridization and immunohistochemistry with probes of collecting duct differentiation. Additional differentiation markers for collecting duct cells will be identified. We further hypothesize that the arrested differentiation in the collecting duct is due to the absence of a maturation factor, specifically epidermal growth factor (EGF). To test this hypothesis we will evaluate EGF gene expression in the kidneys of inherited and induced models of infantile PKD. In addition, we will directly determine the capability of EGF to induce collecting duct cells to differentiate in vitro. EGF will also be administered to mice and rabbits with inherited and induced forms of infantile PKD to determine if EGF inhibits cyst development and promotes epithelial differentiation in vivo. We anticipate that these studies will elucidate the role of renal epithelial immaturity in the pathogenesis of renal cysts.